Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli. Therapeutic agents for asthma are classified into drug for directly relaxing the contraction of the airway or drug for anti-inflammatory action and, for example, include .beta.-2 antagonist, steroids, phosphodiesterase inhibitor, muscarinic antagonist, mucosa, et al.
Phosphodiesterase IV is an enzyme that specifically hydrolyzes cAMP(adenosine 3',5'-cyclic monophosphate) into inactive adenosine 3',5'-mono-phosphate. The cAMP has been shown to be a second messenger mediating the cellular responses to external stimuli and to function to relax or contradict bronchial muscles.
The inhibition of phosphodiesterase IV leads to prevention of broncospasm by maintaining the concentration of cAMP and also induces an anti-inflammation. Therefore, compounds that inhibit phosphodiesterase IV should be effective in treating asthma and the like diseases.
EP Publication No. 232,199 B1 discloses phosphodiesterase IV-inhibiting phenyl derivatives useful in treatment of allergic and inflammatory disease, which are represented as follows. ##STR2##
WO92/12961 discloses compounds of the following formula, which inhibit adenosine cyclic phosphate phosphodiesterase. However, WO92/12961 does not mention any inhibitory activity of TNF by the said compounds. ##STR3##
EP Publication No. 497,564 A1 discloses compounds effective in inhibiting adenosine cyclic 3',5'-phosphate phosphodiesterase IV, which are represented as follows: ##STR4##